An Unusual Case of Anti-Glomerular Basement Membrane Disease and Phospholipase A2 Receptor-Associated Membranous Nephropathy After Exposure to Hydrocarbons.

We present a rare case of a patient with toluene exposure manifesting as anti-glomerular basement membrane (GBM) disease on a background of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy. A 23-year-old man presented to the emergency department with hypertension, headache, hemoptysis, anemia, acute kidney injury, glomerular hematuria, and proteinuria. He endorsed repeated exposure to toluene-containing products while repairing dirt bikes. Serologies were positive for anti-GBM antibodies. Kidney biopsy showed crescentic glomerulonephritis with linear immunoglobulin G and granular PLA2R staining by immunofluorescence. He was initially treated with high-dose steroids, plasmapheresis, and hemodialysis for pulmonary-renal syndrome followed by oral cyclophosphamide and prednisone, which were discontinued after 3 months when follow-up biopsies confirmed little chance for renal recovery. He remained on dialysis 1 year later. This case exhibits a unique presentation of anti-GBM syndrome and underlying membranous nephropathy following repeated hydrocarbon exposure. Inhaled toxins promote recurrent localized inflammation, unmasking previously hidden epitopes. Early diagnosis and appropriate use of immunosuppressive and extracorporeal therapies are necessary to prevent morbidity and to improve survival in this rare condition.

A Murine Model for Enhancement of Streptococcus pneumoniae Pathogenicity upon Viral Infection and Advanced Age.

Streptococcus pneumoniae (pneumococcus) resides asymptomatically in the nasopharynx (NP) but can progress from benign colonizer to lethal pulmonary or systemic pathogen. Both viral infection and aging are risk factors for serious pneumococcal infections. Previous work established a murine model that featured the movement of pneumococcus from the nasopharynx to the lung upon nasopharyngeal inoculation with influenza A virus (IAV) but did not fully recapitulate the severe disease associated with human coinfection. We built upon this model by first establishing pneumococcal nasopharyngeal colonization, then inoculating both the nasopharynx and lungs with IAV. In young (2-month-old) mice, coinfection triggered bacterial dispersal from the nasopharynx into the lungs, pulmonary inflammation, disease, and mortality in a fraction of mice. In aged mice (18 to 24 months), coinfection resulted in earlier and more severe disease. Aging was not associated with greater bacterial burdens but rather with more rapid pulmonary inflammation and damage. Both aging and IAV infection led to inefficient bacterial killing by neutrophils ex vivo. Conversely, aging and pneumococcal colonization also blunted alpha interferon (IFN-α) production and increased pulmonary IAV burden. Thus, in this multistep model, IAV promotes pneumococcal pathogenicity by modifying bacterial behavior in the nasopharynx, diminishing neutrophil function, and enhancing bacterial growth in the lung, while pneumococci increase IAV burden, likely by compromising a key antiviral response. Thus, this model provides a means to elucidate factors, such as age and coinfection, that promote the evolution of S. pneumoniae from asymptomatic colonizer to invasive pathogen, as well as to investigate consequences of this transition on antiviral defense.

The Syndrome of Tubulointerstitial Nephritis With Uveitis (TINU).

The syndrome of tubulointerstitial nephritis and uveitis (TINU) is a multisystemic autoimmune disorder that may occur in response to various environmental triggers, including drugs and microbial pathogens. Evidence exists of HLA antigen-related genetic predisposition to developing TINU. The resulting inflammation affects chiefly the ocular uvea and renal tubules, although other organs may be involved. TINU is uncommon; only about 200 cases are on record since its original description 40 years ago, although it is possible that new ones are no longer being reported. Although its incidence is highest in children and adolescents, all ages may be affected. Renal and ocular inflammation may be clinically severe and persistent, but the prognosis for the majority of patients with TINU is favorable. Owing to its low prevalence, no standard therapeutic protocols have been established, but most reported cases have been treated with corticosteroids or other immunomodulatory agents. TINU has many features in common with sarcoidosis, the main clinical entity from which it must be distinguished. This article begins with an illustrative case vignette, followed by an overview of the syndrome and current theories regarding its pathogenesis.

Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells.

Multiple sclerosis (MS) is an inflammatory disease of the CNS that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons, and axons. Historically, MS has been thought to be a CD4 T cell-mediated autoimmune disease of CNS white matter. However, recent studies identified CD8 T cell infiltrates and gray matter lesions in MS patients. These findings suggest that CD8 T cells and CNS Ags other than myelin proteins may be involved during the MS disease process. In this article, we show that CD8 T cells reactive to glial fibrillary acidic protein (GFAP), a protein expressed in astrocytes, can avoid tolerance mechanisms and, depending upon the T cell-triggering event, drive unique aspects of inflammatory CNS autoimmunity. In GFAP-specific CD8 TCR-transgenic (BG1) mice, tissue resident memory-like CD8 T cells spontaneously infiltrate the gray matter and white matter of the CNS, resulting in a relapsing-remitting CNS autoimmunity. The frequency, severity, and remissions from spontaneous disease are controlled by the presence of polyclonal B cells. In contrast, a viral trigger induces GFAP-specific CD8 T effector cells to exclusively target the meninges and vascular/perivascular space of the gray and white matter of the brain, causing a rapid, acute CNS disease. These findings demonstrate that the type of CD8 T cell-triggering event can determine the presentation of distinct CNS autoimmune disease pathologies.

Viral antigen density and confinement time regulate the reactivity pattern of CD4 T-cell responses to vaccinia virus infection.

T-cell recognition of ligands is polyspecific. This translates into antiviral T-cell responses having a range of potency and specificity for viral ligands. How these ligand recognition patterns are established is not fully understood. Here, we show that an activation threshold regulates whether robust CD4 T-cell activation occurs following viral infection. The activation threshold was variable because of its dependence on the density of the viral peptide (p)MHC displayed on infected cells. Furthermore, the activation threshold was not observed to be a specific equilibrium affinity (K(D)) or half-life (t(1/2)) of the TCR-viral pMHC interaction, rather it correlated with the confinement time of TCR-pMHC interactions, i.e., the half-life (t(1/2)) of the interaction accounting for the effects of TCR-pMHC rebinding. One effect of a variable activation threshold is to allow high-density viral pMHC ligands to expand CD4 T cells with a variety of potency and peptide cross-reactivity patterns for the viral pMHC ligand, some of which are only poorly activated by infections that produce a lower density of the viral pMHC ligand. These results argue that antigen concentration is a key component in determining the pattern of K(D), t(1/2) and peptide cross-reactivity of the TCRs expressed on CD4 T cells responding to infection.

The ability of an attaching and effacing pathogen to trigger localized actin assembly contributes to virulence by promoting mucosal attachment.

Enterohaemorrhagic Escherichia coli (EHEC) colonizes the intestine and causes bloody diarrhoea and kidney failure by producing Shiga toxin. Upon binding intestinal cells, EHEC triggers a change in host cell shape, generating actin 'pedestals' beneath bound bacteria. To investigate the importance of pedestal formation to disease, we infected genetically engineered mice incapable of supporting pedestal formation by an EHEC-like mouse pathogen, or wild type mice with a mutant of that pathogen incapable of generating pedestals. We found that pedestal formation promotes attachment of bacteria to the intestinal mucosa and vastly increases the severity of Shiga toxin-mediated disease.

Jagged2-signaling promotes IL-6-dependent transplant rejection.

The Notch pathway is an important intercellular signaling pathway that plays a major role in controlling cell fate. Accumulating evidence indicates that Notch and its ligands present on antigen-presenting cells might be important mediators of T helper cell differentiation. In this study, we investigated the role of Jagged2 in murine cardiac transplantation by using a signaling Jagged2 mAb (Jag2) that activates recombinant signal-binding protein-Jκ. While administration of Jag2 mAb had little effect on graft survival in the fully allogeneic mismatched model BALB/c→B6, it hastened rejection in CD28-deficient recipients. Similarly, Jag2 precipitated rejection in the bm12→B6 model. In this MHC class II-mismatched model, allografts spontaneously survive for >56 days due to the emergence of Treg cells that inhibit the expansion of alloreactive T cells. The accelerated rejection was associated with upregulation of Th2 cytokines and proinflammatory cytokine IL-6, despite expansion of Treg cells. Incubation of Treg cells with recombinant IL-6 abrogated their inhibitory effects in vitro. Furthermore, neutralization of IL-6 in vivo protected Jag2-treated recipients from rejection and Jagged2 signaling was unable to further accelerate rejection in the absence of Treg cells. Our findings therefore suggest that Jagged2 signaling can affect graft acceptance by upregulation of IL-6 and consequent resistance to Treg-cell suppression.

The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo.

Programmed death-1 ligand 1 (PD-L1) is a coinhibitory molecule that negatively regulates multiple tolerance checkpoints. In the NOD mouse model, PD-L1 regulates the development of diabetes. PD-L1 has two binding partners, programmed death-1 and B7-1, but the significance of the PD-L1:B7-1 interaction in regulating self-reactive T cell responses is not yet clear. To investigate this issue in NOD mice, we have compared the effects of two anti-PD-L1 Abs that have different blocking activities. Anti-PD-L1 mAb 10F.2H11 sterically and functionally blocks only PD-L1:B7-1 interactions, whereas anti-PD-L1 mAb 10F.9G2 blocks both PD-L1:B7-1 and PD-L1:programmed death-1 interactions. Both Abs had potent, yet distinct effects in accelerating diabetes in NOD mice: the single-blocker 10F.2H11 mAb was more effective at precipitating diabetes in older (13-wk-old) than in younger (6- to 7-wk-old) mice, whereas the dual-blocker 10F.9G2 mAb rapidly induced diabetes in NOD mice of both ages. Similarly, 10F.2H11 accelerated diabetes in recipients of T cells from diabetic, but not prediabetic mice, whereas 10F.9G2 was effective in both settings. Both anti-PD-L1 mAbs precipitated diabetes in adoptive transfer models of CD4(+) and CD8(+) T cell-driven diabetes. Taken together, these data demonstrate that the PD-L1:B7-1 pathway inhibits potentially pathogenic self-reactive effector CD4(+) and CD8(+) T cell responses in vivo, and suggest that the immunoinhibitory functions of this pathway may be particularly important during the later phases of diabetogenesis.

The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo.

The programmed death ligand 1 (PDL1)/programmed death 1 (PD1) costimulatory pathway plays an important role in the inhibition of alloimmune responses as well as in the induction and maintenance of peripheral tolerance. It has been demonstrated recently that PDL1 also can bind B7.1 to inhibit T cell responses in vitro. Using the bm12 into B6 heart transplant model, we investigated the functional significance of this interaction in alloimmune responses in vivo. PD1 blockade unlike PDL1 blockade failed to accelerate bm12 allograft rejection, suggesting a role for an additional binding partner for PDL1 other than PD1 in transplant rejection. PDL1 blockade was able to accelerate allograft rejection in B7.2-deficient recipients but not B7.1-deficient recipients, indicating that PDL1 interaction with B7.1 was important in inhibiting rejection. Administration of the novel 2H11 anti-PDL1 mAb, which only blocks the PDL1-B7.1 interaction, aggravated chronic injury of bm12 allografts in B6 recipients. Aggravated chronic injury was associated with an increased frequency of alloreactive IFN-γ-, IL-4-, and IL-6-producing splenocytes and a decreased percentage of regulatory T cells in the recipients. Using an in vitro cell culture assay, blockade of the interaction of PDL1 on dendritic cells with B7.1 on T cells increased IFN-γ production from alloreactive CD4(+) T cells, whereas blockade of dendritic cell B7.1 interaction with T cell PDL1 did not. These data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL1 and B7.1 interaction.

Auto-antibody production and glomerulonephritis in congenic Slamf1-/- and Slamf2-/- [B6.129] but not in Slamf1-/- and Slamf2-/- [BALB/c.129] mice.

Several genes in an interval of human and mouse chromosome 1 are associated with a predisposition for systemic lupus erythematosus. Congenic mouse strains that contain a 129-derived genomic segment, which is embedded in the B6 genome, develop lupus because of epistatic interactions between the 129-derived and B6 genes, e.g. in B6.129chr1b mice. If a gene that is located on chromosome 1 is altered through homologous recombination in 129-derived embryonic stem cells (ES cells) and if the resultant knockout mouse is backcrossed with B6, interpretation of the phenotype of the mutant mouse may be affected by epistatic interactions between the 129 and B6 genomes. Here, we report that knockout mice of two adjacent chromosome 1 genes, Slamf1(-/-) and Slamf2(-/-), which were generated with the same 129-derived ES cell line, develop features of lupus, if backcrossed on to the B6 genetic background. By contrast, Slamf1(-/-) [BALB/c.129] and Slamf2(-/-) [BALB/c.129] do not develop disease. Surprisingly, Slamf1(-/-) [B6.129] mice develop both auto-antibodies and glomerulonephritis between 3 and 6 months of age, while disease fully develops in Slamf1(-/-) [B6.129] mice after 9-14 months. Functional analyses of CD4(+) T cells reveals that Slamf2(-/-) T cells are resistant to tolerance induction in vivo. We conclude that the Slamf2(-/-) mutation may have a unique influence on T-cell tolerance and lupus.

Pseudogout: A Rare Cause of Acute Carpal Tunnel Syndrome and Acute Guyon Canal Syndrome.

Pseudogout is an acute inflammatory arthropathy that often presents as a hot, swollen, painful joint. Rarely, the inflammatory response caused by pseudogout has led to acute neuropathic symptoms of the hand. We present a case of pseudogout causing acute neuropathic symptoms in the median and ulnar nerves, ultimately necessitating urgent surgical decompression. The patient's symptoms were alleviated after surgical decompression. Pseudogout should be considered a rare cause of acute neuropathic compression of the hand. Its management may require surgical intervention and should involve postoperative follow-up with a rheumatologist.

Encapsulating Peritoneal Sclerosis Presenting after Two Donor Kidney Transplantations: A Case Report and Literature Review.

Encapsulating peritoneal sclerosis is a rare, recurring complication in peritoneal dialysis (PD) patients. With a mortality rate of 51%, it continues to be a therapeutic enigma among clinicians. However, the incidence after kidney transplantation (KT) has rarely been reported. We report a unique case of encapsulating peritoneal sclerosis (EPS), occurring years after failed initial living KT, and diagnosed after second deceased donor kidney transplantation. A 35-year-old male, on prior PD for 4 years, followed by failed KT of 8 years, was presented with abdominal pain, weight loss, and vomiting, 7 months after his second deceased donor KT. An abdominal computed tomography showed intra-abdominal loculated fluid collection, but no obstruction. Exploratory laparotomy revealed extensive peritoneal thickening and blocked intestinal loops. Histopathology was indicative of EPS with fibrous adhesions and sclerotic tissues. Besides restarting his immunosuppressive medications, tamoxifen therapy was initiated as definitive medical management. Currently, he is in clinical remission, follows at transplant clinic, and still experiences episodes of small bowel obstruction. Though the incidence of EPS after KT has been observed sporadically worldwide, none has been reported in the USA. Despite its prevalence in PD patients, therapeutic interventions attempted so far, are not definitive.

Transplantation of Renal Allograft After Removal of Renal Cell Carcinoma: Case Report and Review of the Literature.

With the rising incidence of end-stage renal disease in the United States, patients needing renal transplants are waiting longer for increasingly scarce grafts. Formerly, the general practice was to avoid organs with tumors for transplant because of the risk of malignancy transmission to the recipient. However, with comprehensive donor selection and a small-sized primary tumor, the positive outcomes of transplant outweigh the risks of transmission after a partial nephrectomy. In our case, a 31-year-old woman, the daughter of the recipient, underwent a laparoscopic nephrectomy with an existing 8-mm tumor later confirmed as renal cell carcinoma. An ex vivo tumor enucleation was performed before the allograft was transplanted into the 69-year-old patient with endstage renal disease. At last follow-up, graft function has remained excellent with no evidence of local recurrence or metastasis in both the donor and recipient. Here, we describe our case and perform a literature review on the incidence and management of renal allografts with incidentally detected renal cell carcinoma during transplant.

Gene Expression Profiling in the Skin Reveals Strong Similarities between Subacute and Chronic Cutaneous Lupus that Are Distinct from Lupus Nephritis.

Subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are represented in the majority of cutaneous lupus subtypes, each of which has variable implications for systemic manifestations such as lupus nephritis. On dermatologic examination, subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are distinct. However, it is often difficult to diagnose the subtype from histology alone. Our study utilized whole-genome microarray expression analysis on human skin samples of subacute cutaneous lupus erythematosus, on human skin samples of chronic cutaneous lupus erythematosus, and on healthy controls, along with analysis on human samples of lupus nephritis and normal kidney tissue to compare cutaneous lupus subtypes with each other as well as with lupus nephritis. The data revealed that cutaneous lupus subtypes were distinct from healthy control skin, with gene expression predominantly characterized by upregulation of IFN-1 and T-cell chemotactic genes. However, the cutaneous lupus subtypes were very similar to one another; comparative analyses revealed few statistically significant differences in gene expression. There were also distinct differences between the gene signatures of cutaneous lupus and lupus nephritis. Cutaneous lupus samples revealed gene signatures demonstrating a prominent inflammatory component that may suggest the skin as an early site of initiation of lupus pathogenesis, whereas lupus nephritis reflected the recruitment and activation of M2 macrophages and a wound healing signature.

Critical role of donor tissue expression of programmed death ligand-1 in regulating cardiac allograft rejection and vasculopathy.

BACKGROUND: Allograft vasculopathy is a major limiting factor in the long-term success of cardiac transplantation. T cells play a critical role in initiation of cardiac allograft rejection and allograft vasculopathy. The negative T-cell costimulatory pathway PD-1:PDL1/PDL2 (programmed death-1:programmed death ligand-1/2) plays an important role in regulating alloimmune responses. We investigated the role of recipient versus donor PD-1 ligands in the pathogenesis of allograft rejection with emphasis on the role of tissue expression in regulating this alloimmune response in vivo. METHODS AND RESULTS: We used established major histocompatibility complex class II- and class I-mismatched models of vascularized cardiac allograft rejection, blocking anti-PDL1 and anti-PDL2 antibodies, and PDL1- and PDL2-deficient mice (as donors or recipients) to study the role of the PD-1:PDL1/PDL2 pathway in chronic rejection. We also used PDL1-deficient and wild-type mice and bone marrow transplantation to generate chimeric animals that express PDL1 exclusively on either hematopoietic or parenchymal cells. PDL1 but not PDL2 blockade significantly accelerated cardiac allograft rejection in the bm12-into-B6 and B6-into-bm12 models. Although wild-type cardiac allografts survived long term, PDL1-/- donor hearts transplanted into wild-type bm12 mice exhibited accelerated rejection and vasculopathy associated with enhanced recipient T-cell alloreactivity. Interestingly, PDL1-/- recipients did not exhibit an accelerated tempo of cardiac allograft rejection. Using chimeric animals as donors, we show that PDL1 expression on cardiac tissue alone significantly prolonged graft survival compared with full PDL1-/- donor grafts in transplanted wild-type recipients. CONCLUSIONS: This is the first report to demonstrate that expression of the negative costimulatory molecule PDL1 on donor cardiac tissue regulates recipient alloimmune responses, allograft rejection, and vasculopathy.

Robot-Assisted Thoracoscopic Resection of a Posterior Mediastinal Mullerian Cyst.

First described in 2005, the Mullerian derived cyst in the mediastinum is a rare finding with few subsequent reports. We report a case of Mullerian cyst occurring in the mediastinum of a 49-year-old female that was resected by robot-assisted thoracoscopic surgery. To our knowledge, this is the first report of robot-assisted resection of Hattori's cyst. Histopathologic analysis revealed ciliated Mullerian-type tubal epithelium positive for paired box gene 8 (PAX8), estrogen receptor (ER), and progesterone receptor (PR), confirming Mullerian differentiation. We also review the clinical presentation, pathology, and differential diagnosis of such cysts.

Sensitivity of P504S/alpha-methylacyl-CoA racemase (AMACR) immunohistochemistry for the detection of prostate carcinoma on stored needle biopsies.

Alpha methylacyl-CoA-racemase (AMACR), also known as P504S, has been widely used as a positive marker for the diagnosis of prostate carcinoma in clinical practice. The utility of this assay is highly dependent on the sensitivity of AMACR detection in routinely processed biopsies. It is common practice to store precut prostate biopsy sections. Hence, it is important to determine the effect on the immunoreactive of P504S/AMACR in stored, unstained glass slides as compared with freshly cut sections of paraffin-embedded tissue. The purpose of this study was to determine the sensitivity of AMACR immunostaining for the detection of prostate carcinoma on stored needle biopsies. A total of 63 prostate biopsies with prostate carcinoma were transferred onto glass slides, baked, and stored for 1.6 to 9.2 months. The Gleason scores were 3+3(6) (n=40) including 10 small focal carcinomas (< or = 1.0 mm), 4+3(7) (n=16), and 4+4(8) or higher (n=7). The slides were then stained with a monoclonal antibody to P504S, and the staining intensity was compared with sections cut from the same blocks just prior to immunostaining, without an intervening storage period. There was no loss of sensitivity of AMACR for prostate adenocarcinoma, regardless of the length of the storage interval. The sensitivity was preserved and was independent of Gleason scores. The sensitivity of AMACR for small foci of adenocarcinoma was also not affected by the length of storage. Overall, stored slides had no observable increase in nonspecific background staining over freshly cut sections. These results indicate that the time interval between mounting and staining does not affect the sensitivity of the AMACR immunohistochemistry (IHC) stain in the detection of prostate cancer even with small foci of carcinoma on needle biopsies.

Acute kidney injury due to intravenous bleach injection.

INTRODUCTION: Sodium hypochlorite is the active ingredient in bleach, a ubiquitous household disinfectant, and has known toxicities depending on route of exposure and amount. Acute kidney injury due to sodium hypochlorite exposure has never been reported. Patients that did develop nephrotoxicity following bleach exposure did so due to development of other risk factors for kidney injury such as volume depletion or sepsis. DISCUSSION: We report a patient who presented with black urine after parenteral self-administration of a large quantity of bleach. We review the clinical presentation, laboratory and biopsy findings, and outcome as well as discuss possible mechanisms of sodium hypochlorite toxicity and management strategies.